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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
fertility, other
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study well documented, meets generally accepted scientific principles, acceptable for assessment. Data and Rating according to the SIDS 2005 on barium cabonate. Deviances when comparing to OECD421: dosing only prior to mating, no individual animal data/tables provided, histopathologic examination, data on food consumption only provided for core study animals, no humidity, sex of pups, and data on stability of test substance in vehicle given. Only the average results of the controls and the high dose groups of each species were available.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Subchronic toxicity of barium chloride dihydrate administered to rats and mice in the drinking water.
Author:
Dietz, D.D.; et al.
Year:
1992
Bibliographic source:
Fund. Appl. Tox. 19, 527-537

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
In parallel with a subchronic toxicity core study, a premating study was performed with separate groups of rats and mice. Premating exposure period with Barium chloride dihydrate was 60 days for males and 30 days for females.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline
Details on test material:
- Name of test material (as cited in study report): Barium chloride dihydrate
- EC number: 233-788-1
- Molecular formula (if other than submission substance): BaCl2 x 2H2O
- Molecular weight (if other than submission substance): 226.3 g (calculated from molecular formula)
- Smiles notation (if other than submission substance):
- InChl (if other than submission substance):
- Structural formula attached as image file (if other than submission substance): see Fig.
- Substance type: technical product
- Physical state: white, crystalline solid
- Analytical purity: 99.5 % (by EDTA titration)
- Lot/batch No.: 123120 (from Baker Chemical Co., Phillipsburg, NJ)
- no further significant details stated

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Simonson Laboratories, Gilroy, CA
- Age at study initiation: (P) 32 days
- Housing: five per cage in drawer-type polycarbonate cages (shelves covered with filter sheets, bedding, cages and water bottles were changed twice a week, feeders once a week, racks and filters every other week); after 60 days of exposure, the males were placed in individual cages and one female receiving the same dose level (but exposed for 30 days) was cohabited with the male. After mating the females were separated.
- Diet: NIH-o7 pellets (Ziegler Brothers, Gardners, PA)
- Water: ad libitum (dosed or undosed) for 92 consecutive days
- Acclimation period: 10 to 11 days (quarantined)


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 24 °C
- Air changes (per hr): 13.5 room vol.
- Photoperiod (hrs dark / hrs light): 12/12 (fluorescent lighting)

- no further significant details stated

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Solutions were made weekly in 19-liter quantities by dissolving weighed portions of the test substance in glass-distilled water.
- Concentration in vehicle: 0, 500, 1000 and 2000 ppm
- no further significant details stated
Details on mating procedure:
- M/F ratio per cage: 1 male / 1 female mouse
- Length of cohabitation: up to one week
- Proof of pregnancy:Examination for the presence of a vaginal plug every morning
- When evidence of mating was found, the females was separated from the males.
- After mating determinations were made on the eighth day of cohabition and all remaining pairs were separated.
- No remating was performed although pregnancy rate was low.
- no further significant details stated


Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses were performed on all levels before and after use, and at the beginning and midway through the test period. The concentrations were within 1 to 6 % of the theoretical concentration. Method of analysis was not stated.
Duration of treatment / exposure:
Premating exposure period: 60 days for males and 30 days for females
Frequency of treatment:
continuous
Details on study schedule:
- no further significant details stated
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
500 ppm BaCl2 * 2H2O
Basis:
nominal in water
calculated average dose: 52.9 mg Ba/kg bw/d to males and 58.9 mg Ba/kg bw/d to females
Remarks:
Doses / Concentrations:
1000 ppm BaCl2 * 2H2O
Basis:
nominal in water
calculated average dose: 102.5 mg Ba/kg bw/d to males and 105.2 mg Ba/kg bw/d to females
Remarks:
Doses / Concentrations:
2000 ppm BaCl2 * 2H2O
Basis:
nominal in water
calculated average dose: 206 mg Ba/kg bw/d to males and 199.8 mg Ba/kg bw/d to females
No. of animals per sex per dose:
20 male and 20 female mice
Control animals:
yes, concurrent vehicle
Details on study design:
- Other: No remating was performed due to restriction in the study dosing schedule/design.
- no further significant details stated
Positive control:
not required

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily


CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily


BODY WEIGHT: Yes
- Time schedule for examinations: weekly and females were weighed when evidence of mating was found an on the day of parturition.


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: twice weekly


OTHER:
- determination of pregnancy rates in dosed and control animals
- determination of average gestation period
- no further significant details stated
Oestrous cyclicity (parental animals):
- Evaluation of vaginal cytology was performed among treated and control groups.
Sperm parameters (parental animals):
Parameters examined in P male parental generations:
- An evaluation of sperm morphology, density, and motility and sperm count was performed among treated and control groups.
- no further significant details stated
Litter observations:
PARAMETERS EXAMINED
The following examinations were performed in F1 offspring:
- pups were examined at birth and day 5
- number of live litter, average litter size at day 0 and 5, pup survival to day 5, pup weight at birth and day 5, external abnormalities

GROSS EXAMINATION OF DEAD PUPS:
- yes, dead pups were examined for external abnormalities

- no further significant details stated
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: not stated
- Maternal animals: All surviving animals were terminated on days 96 and 97.

GROSS NECROPSY
- The vagina, cervix, oviducts, and ovaries were grossly examined and the implantation sites in the uteri were counted.
- The male reproductive organ weights (testis, epidimymal) was determined among treated and control groups.

HISTOPATHOLOGY / ORGAN WEIGHTS
- Complete histologic exams were performed in the parallel animal groups (core study) which were not used for reproductive and fertility assessment.

- no further significant details stated
Postmortem examinations (offspring):
- no data
Statistics:
Each parameter for which individual values were available was subjected to a linear least squares regression over the doselevels and the direction of the slope and the p value indicating the significance of the deviation of the slope from 0 was determined. Group means and standard deviations or standard errors were calculated for continuous variables. The multiple comparison procedure of Dunnett (1955) was used for comparison between dosed and control groups. Further, Fisher's extract test, the Cochran-Armitage test (Armitage, 1971; Gart et al., 1979) was used as well as repeated measures analysis of variance (WInter, 1971) and a multivariate analysis of variance (Morrison, 1976).
Reproductive indices:
- no significant details stated
Offspring viability indices:
- no significant details stated

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
- no evidence of maternal toxicity in the treated mice

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
- maternal weight gain during pregnancy was comparable to controls for all groups.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
- only determined for core study animals

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
- There were no treatment-related effects of barium chloride dihydrate on vaginal cytology up to 2000 ppm.


REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
- There were no treatment-related effects of barium chloride dihydrate on epididymal sperm count, sperm motility, sperm morphology, up to 2000 ppm.


REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
- The pregnancy rates in mice were 55 % in the controls and ranged from 55 - 70 % in the treated groups.
- All pregnant mice produced live litters
- The average gestation period of the control and test mice ranged from 18.5 to 18.9 days.


ORGAN WEIGHTS (PARENTAL ANIMALS)
- no effect could be detected on testis or epididymal weight


GROSS PATHOLOGY (PARENTAL ANIMALS)
- Necropsy revealed no evidence of pregnancy in mice that did not produce viable offspring.

- no further significant details stated

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
2 000 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: fertility impairment

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined

Details on results (F1)

VIABILITY (OFFSPRING)
- a few pups were found dead at birth in any group, and survival from birth to postpartum Day 5 ranged from 98 to 100 %

CLINICAL SIGNS (OFFSPRING)
- No external abnormalities were observed in any of the offspring..

BODY WEIGHT (OFFSPRING)
- No statistical differences in live pup body weights.

OTHER
- The average litter size at birth and on postpartum day 5 was statistically significant reduced for the mice of the 1000 ppm group compared with the controls (Day 0, 10.7+/-0.40 pups compared to 7.9+/- 1.02 pups; Day 5, 10.8+/-0.38 pups compared to 7.7+/-0.97 pups; p<0.05). But the avaerage live litter size of the highest dose group (2000 ppm) approximated that of the controls.

- no further significant details stated

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
2 000 ppm (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: development toxicity, but the NOAEL is of limited value to evaluate the potential for barium to induce developmental effects

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Only the average results of the controls and the high dose groups of each species were available.

No-observed-adverse-effect level (NOAEL) for fertility impairment was 2,000ppm in mice. These NOAEL values correspond to average doses of 206 and 199.8 mg Ba/kg bw/d to male and and female mice, respectively.

A NOAEL on developmental toxicity of 2,000 ppm is also reported. However, the NOAEL is of limited value to evaluate the potential for barium to induce developmental effects. The reason for this limitation is based on the fact that the premating study design did not include exposure of female animals during the gestational period to barium chloride. Therefore, the premating study has to be considered as an inadequate study of developmental toxicity and cannot be used to determine the occurrence of developmental toxicity.

Applicant's summary and conclusion

Conclusions:
Taken together all data of this study, there are no indications of a substantial impairment of fertility in mice up to the highest dose tested. Thus, the NOAEL was 2000 ppm (to average doses of 206 and 199.8 mg Ba/kg bw/d to male and and female mice, respectively). No-observed-adverse-effect levels (NOAELs) on developmental toxicity for mice of 2000 ppm were derived from this study. However, this NOAEL is of limited value to evaluate the potential for barium to induce developmental effects because there was no exposure of the females during gestation.